Severe acute respiratory syndrome (SARS) is a potentially fatal disease that appears to have originated in the Guandong Province of China in the fall of 2002. The disease is caused by a new human coronavirus (CoV), named the SARS-CoV. SARS-CoV produces a highly pathogenic disease with increase mortality compared to other human coronaviruses. The viral basis for this increase pathogenesis has not been identified. We have shown that the SARS-CoV is able to modulate the innate immune response during infection. This application aims to characterize two newly identified viral proteins that we have shown are able to modify the Interferon response in cells. I have identified two virally encoded proteins that are able to block Interferon induction and signaling in cells. We will investigate the mechanism of action of the immune modulating proteins using cell biological and biochemical techniques. We will further characterize the function of the SARS proteins in vivo, using our reverse genetic system for SARS which enables us to delete or mutate the genes in question and evaluate the effects of those mutations on viral pathogenesis in a mouse model of SARS infection. Using a newly created mouse adapted SARS virus, which unlike the wild type isolates of SARS, does cause significant pathology and death in mice, we will elucidate the mechanism that immune modifying proteins of the virus have on the pathological outcome of disease. The SARS Coronavirus is a model organism to investigate the effects of virus infection on lung pathology. Identification of the pathway of lung damage and disease progression in SARS will enable better understanding and potential new targets for drugs to combat the worldwide burden of lung diseases. When ranking the global burden of disease, the WHO identifies lung disease as the most prevalent type of disease in the world, outranking HIV/AIDS, diarrheal disease, Malaria and Tuberculosis. Identification of the genes and mechanisms contributing to SARS pathogenesis and pathology may lead directly to better treatment options for other lung diseases.